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Biomarkers for anti-vascular endothelial growth factor drugs.

ABSTRACT: Angiogenesis is regulated by interactions between vascular endothelial growth factors (VEGFs) and VEGF receptors. VEGF-A, VEGF-D, placental growth factor (PlGF) and plasminogen activator inhibitor-1 (PAI-1) have tumor angiogenic activity. VEGF-A and PAI-1 levels in the blood may impact the activity of bevacizumab, and VEGF-D levels may similarly diminish the efficacy of ramucirumab. However, the dynamics of these angiogenic biomarkers for anti-VEGF therapy have not been well established; therefore, they were evaluated in this retrospective study, which included two cohorts. Cohort 1 included patients who were treated with cytotoxic agents and bevacizumab as first-line chemotherapy, and Cohort 2 comprised patients who were treated with cytotoxic agents and anti-VEGF drugs (bevacizumab, ramucirumab or aflibercept) as second-line chemotherapy. VEGF-A, VEGF-D, PlGF and PAI-1 levels were measured before starting chemotherapy and were re-assessed every 1-2 months until disease progression. Bevacizumab had reduced benefit as a first-line chemotherapeutant in patients with very low or very high levels of VEGF-A. Bevacizumab increased VEGF-A and PlGF levels, but not VEGF-D or PAI-1. Anti-VEGF drugs offered the greatest benefit to patients with high PAI-1 before first- and second-line chemotherapy. PAI-1 levels were not affected by anti-VEGF drugs. Since ramucirumab increased VEGF-D, it offered less benefit to patients with high VEGF-D in second-line chemotherapy. Conversely, aflibercept offered greater benefits to patients with high VEGF-D, without increasing VEGF-D. These biomarkers may be useful for the prediction of drug efficacy and may predict resistance to anti-VEGF drugs.

SUBMITTER: Kuriyama S

PROVIDER: S-EPMC9667458 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Biomarkers for anti-vascular endothelial growth factor drugs.

Kuriyama Sho S Yamada Takeshi T Matsuda Akihisa A Takahashi Goro G Iwai Takuma T Takeda Kohki K Ueda Koji K Miyasaka Toshimitsu T Yokoyama Yasuyuki Y Shinji Seiichi S Sonoda Hiromichi H Ohta Ryo R Yonaga Kazuhide K Kanaka Shintaro S Yoshida Hiroshi H

Oncology letters 20221107 6

Angiogenesis is regulated by interactions between vascular endothelial growth factors (VEGFs) and VEGF receptors. VEGF-A, VEGF-D, placental growth factor (PlGF) and plasminogen activator inhibitor-1 (PAI-1) have tumor angiogenic activity. VEGF-A and PAI-1 levels in the blood may impact the activity of bevacizumab, and VEGF-D levels may similarly diminish the efficacy of ramucirumab. However, the dynamics of these angiogenic biomarkers for anti-VEGF therapy have not been well established; therefo ...[more]

PMID: 36406183

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Project description:BackgroundNeovascular glaucoma (NVG) is a potentially blinding secondary glaucoma. It is caused by the formation of abnormal new blood vessels which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) agents are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGFs for the control of intraocular pressure (IOP) in NVG.ObjectivesTo compare the IOP lowering effects of intraocular anti-VEGF agents to no anti-VEGF treatment, as an adjunct to existing modalities for the treatment of NVG.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 January 2013.Selection criteriaWe included randomized controlled trials (RCTs) and quasi-RCTs of people treated with anti-VEGF agents for NVG.Data collection and analysisTwo authors independently assessed the search results for trials to be included in the review. Discrepancies were resolved by discussion with a third author. Since no trial met our inclusion criteria, no assessment of risk of bias or meta-analysis was undertaken.Main resultsNo RCTs were found that met the inclusion criteria for this review. Two RCTs of anti-VEGF agents for treating NVG were not included in the review due to the heterogeneity and uncontrolled assignment of adjunct treatments received by the study participants.Authors' conclusionsCurrently available evidence is insufficient to evaluate the effectiveness of anti-VEGF treatments, such as intravitreal ranibizumab or bevacizumab, as an adjunct to conventional treatment in lowering IOP in NVG. Well designed RCTs are needed to address this issue, particularly trials that evaluate long-term (at least six months) benefits and risks since the effects of anti-VEGF agents may be short-term only. An RCT comparing anti-VEGF agents with no anti-VEGF agents taking into account the need for co-interventions, such as panretinal photocoagulation (PRP), glaucoma shunt procedures, cyclodestructive procedures, cataract surgery, and deep vitrectomy, could be of use to investigate the additional beneficial effect of anti-VEGF agents in treating NVG. Since decisions for when and which co-interventions should be used are based on clinical criteria, they would not be appropriate for randomization. However, the design of a study on this topic should aim to balance groups by stratification of co-intervention at time of randomization or by enrolling a sufficient number of participants to conduct subgroup analysis by co-interventions (ideally 15 participants per treatment group for each subgroup). Alternatively, the inclusion criteria for a trial could limit participants to those who receive the same co-intervention.

Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

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Biomarkers for anti-vascular endothelial growth factor drugs.

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Biomarkers for anti-vascular endothelial growth factor drugs.

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